Physical and functional interaction between the α- and γ-secretases: A new model of regulated intramembrane proteolysis

Many single-transmembrane proteins are sequentially cleaved by ectodomain-shedding α-secretases and the γ-secretase complex, a process called regulated intramembrane proteolysis (RIP). These cleavages are thought to be spatially and temporally separate. In contrast, we provide evidence for a hitherto unrecognized multiprotease complex containing both α- and γ-secretase. ADAM10 (A10), the principal neuronal α-secretase, interacted and cofractionated with γ-secretase endogenously in cells and mouse brain. A10 immunoprecipitation yielded γ-secretase proteolytic activity and vice versa. In agreement, superresolution microscopy showed that portions of A10 and γ-secretase colocalize. Moreover, multiple γ-secretase inhibitors significantly increased α-secretase processing (r = −0.86) and decreased β-secretase processing of β-amyloid precursor protein. Select members of the tetraspanin web were important both in the association between A10 and γ-secretase and the γ→α feedback mechanism. Portions of endogenous BACE1 coimmunoprecipitated with γ-secretase but not A10, suggesting that β- and α-secretases can form distinct complexes with γ-secretase. Thus, cells possess large multiprotease complexes capable of sequentially and efficiently processing transmembrane substrates through a spatially coordinated RIP mechanism.     

The Tyrosine Kinase c-Abl Promotes Homeodomain-interacting Protein Kinase 2 (HIPK2) Accumulation and Activation in Response to DNA Damage

The non-receptor tyrosine kinase c-Abl is activated in response to DNA damage and induces p73-dependent apoptosis. Here, we investigated c-Abl regulation of the homeodomain-interacting protein kinase 2 (HIPK2), an important regulator of p53-dependent apoptosis. c-Abl phosphorylated HIPK2 at several sites, and phosphorylation by c-Abl protected HIPK2 from degradation mediated by the ubiquitin E3 ligase Siah-1. c-Abl and HIPK2 synergized in activating p53 on apoptotic promoters in a reporter assay, and c-Abl was required for endogenous HIPK2 accumulation and phosphorylation of p53 at Ser⁴⁶ in response to DNA damage by γ- and UV radiation. Accumulation of HIPK2 in nuclear speckles and association with promyelocytic leukemia protein (PML) in response to DNA damage were also dependent on c-Abl activity. At high cell density, the Hippo pathway inhibits DNA damage-induced c-Abl activation. Under this condition, DNA damage-induced HIPK2 accumulation, phosphorylation of p53 at Ser⁴⁶, and apoptosis were attenuated. These data demonstrate a new mechanism for the induction of DNA damage-induced apoptosis by c-Abl and illustrate network interactions between serine/threonine and tyrosine kinases that dictate cell fate.     

Historical Outbreaks of Simian Hemorrhagic Fever in Captive Macaques Were Caused by Distinct Arteriviruses

Simian hemorrhagic fever (SHF) is lethal for macaques. Based on clinical presentation and serological diagnosis, all reported SHF outbreaks were thought to be caused by different strains of the same virus, simian hemorrhagic fever virus (SHFV; Arteriviridae). Here we show that the SHF outbreaks in Sukhumi in 1964 and in Alamogordo in 1989 were caused not by SHFV but by two novel divergent arteriviruses. Our results indicate that multiple divergent simian arteriviruses can cause SHF.     

Determining meteorological drivers of salt marsh mosquito peaks in tropical northern Australia

In northern Australia the northern salt marsh mosquito Aedes vigilax is a vector of Ross River virus and is an appreciable pest. A coastal wetland adjacent to Darwin's residential suburbs offers a favorable habitat for Ae. vigilax, and despite vigilant mosquito control efforts, peaks of Ae. vigilax occur in excess of 500/trap/night some months. To improve mosquito control for disease and nuisance biting to nearby residential areas, we sought to investigate meteorological drivers associated with these Ae. vigilax peaks. We fitted a cross‐sectional logistic regression model to weekly counts of female Ae. vigilax mosquitoes collected between July, 1998 and June, 2009 against variables, tide, rainfall, month, year, and larval control. Aedes vigilax peaks were associated with rainfall during the months September to November compared with January, when adjusted for larval control and tide. To maximize mosquito control efficiency, larval control should continue to be implemented after high tides and with increased emphasis on extensive larval hatches triggered by rainfall between September and November each year. This study reiterates the importance of monitoring and evaluating service delivery programs. Using statistical modelling, service providers can obtain solutions to operational problems using routinely collected data. These methods may be applicable in mosquito surveillance or control programs in other areas.     

Modelling both dominance and species distribution provides a more complete picture of changes to mangrove ecosystems under climate change

Dominant species influence the composition and abundance of other species present in ecosystems. However, forecasts of distributional change under future climates have predominantly focused on changes in species distribution and ignored possible changes in spatial and temporal patterns of dominance. We develop forecasts of spatial changes for the distribution of species dominance, defined in terms of basal area, and for species occurrence, in response to sea level rise for three tree taxa within an extensive mangrove ecosystem in northern Australia. Three new metrics are provided, indicating the area expected to be suitable under future conditions (E_occupied), the instability of suitable area (E_instability) and the overlap between the current and future spatial distribution (E_overlap). The current dominance and occurrence were modelled in relation to a set of environmental variables using boosted regression tree (BRT) models, under two scenarios of seedling establishment: unrestricted and highly restricted. While forecasts of spatial change were qualitatively similar for species occurrence and dominance, the models of species dominance exhibited higher metrics of model fit and predictive performance, and the spatial pattern of future dominance was less similar to the current pattern than was the case for the distributions of species occurrence. This highlights the possibility of greater changes in the spatial patterning of mangrove tree species dominance under future sea level rise. Under the restricted seedling establishment scenario, the area occupied by or dominated by a species declined between 42.1% and 93.8%, while for unrestricted seedling establishment, the area suitable for dominance or occurrence of each species varied from a decline of 68.4% to an expansion of 99.5%. As changes in the spatial patterning of dominance are likely to cause a cascade of effects throughout the ecosystem, forecasting spatial changes in dominance provides new and complementary information in addition to that provided by forecasts of species occurrence.